Optogenetics is proving to be highly promising in the treatment of obsessive-compulsive disorders

Thanks to work carried out by the Massachusetts Institute of Technology in Boston, Eric Burguière, an Inserm researcher working in the MHI research centre and his co-workers have succeeded in reducing the compulsive behaviour of mice using optogenetics, a technique that combines light stimulation with genetic engineering.By applying light stimulation to highly specific neurons in the brain, the researchers managed to re-establish normal behaviour in mice that had beforehand presented pathological repetitive behaviour similar to that observed in human patients suffering from obsessive-compulsive disorders.

Repetitive behaviour is characterised by a certain number of neuro-psychiatric disorders, in particular obsessive-compulsive disorders, that develop to such an extent that they become a real handicap to daily life (for example, washing hands up to 30 times a day; or checking excessively that a door is locked, etc.). Obsessive-compulsive disorders affect 2 to 3% of the population and in France, it is estimated that over one million persons are affected by this disorder.

The usual treatment for obsessive-compulsive disorders is to use pharmacological treatments (anti-depressants, neuroleptics) and/or behavioural psychotherapy. However, in spite of these therapeutic combinations, severe symptoms persist in around one third of patients. So it is necessary to gain better understanding of the cerebral mechanisms that cause these repetitive behaviour patterns in order to provide better treatment.

Previous neuroimaging studies allowed us to identify dysfunctioning in neuron circuits located between the front of the brain (the orbitofrontal cortex) and more deep-seated cerebral structures (the ganglions at the base on the brain), in certain persons suffering from obsessive-compulsive disorders.

In this new study, Eric Burguière and his co-workers (in the laboratory of Pr. Ann Graybiel in the MIT) concentrated their research on this neuron circuit in order to both examine its function in detail and also to develop an approach to treating obsessive-compulsive disorders in a mutant mouse model.

In these mutant mice, the obsessive behaviour was expressed by repeated grooming all day long, to such an extent that it caused cutaneous lesions.

From a physiological point of view, these animals are failing to express a protein (caused by the absence of a gene Sapap3) that is normally present in the stratial neuron synapses, a structure that is part of the ganglions at the base of the brain and is involved in functions such as learning sequences, developing habits, or decision-making.

Thanks to these mouse models, initial observations allowed the researchers to show that the emergence of compulsive behaviour in mutant mice was caused by a deficiency in behavioural inhibition. The mice are unable to stop the act of grooming, even when it is no longer necessary. The researchers then used recordings of the neuron activity to show that the dysfunction of communication in the brain between the neocortex and the striatum leads to hyperactivity of stratial neurons in mice.

The use of lighT

In order to check this hypothesis, optogenetics was used. This method consists in modifying the previously identified neurons so as to make them express light-sensitive proteins known as opsins. Since these neuron cells are more sensitive to light, it becomes possible to control their activity by exciting them or inhibiting them using a simple light beam.

When the researchers used light stimulation to excite the neurons in the cortex that send messages to the striatum, the compulsive disorders of the mice were greatly attenuated. On the other hand, when there was no stimulation, the compulsive behaviour recurred.

“Our discoveries show that selective stimulation of the circuit can re-establish normal behaviour in mice that originally presented pathological repetitive behaviour, similar to the type of behaviour observed in certain patients suffering from obsessive-compulsive disorders”, stated Eric Burguière.

This study is promising from a methodological point of view, since it shows that the approach using optogenetics may allow us to identify the role played by neuron circuits in the brain that, if found to be dysfunctional, are liable to cause pathological behaviour.

For researchers, this study has an added interest in the light of its clinical prospects. “I have indeed decided to return to France as part of an Inserm[1] team so that I can run a parallel study on the physiological and behavioural effects of deep cerebral stimulation on patients suffering from obsessive-compulsive disorders, and on mice using the optogenetics technique, in order to get a better understanding of how light stimulation works.”

Discovered in the mid 2000’s, optogenetics is a technique that combines both optics and genetic engineering. It consists in genetically modifying certain neuron cells to make them sensitive to light. What is the aim of this? The aim is to remotely activate or inhibit a specific sub-population of neurons using a light beam, and, unlike electrical stimulation, to do it without affecting the surrounding cells. What is the purpose? The purpose is to study the causal relationships between the activity of the targeted brain pathways and the behaviour controlled by these.

[1] BEBG team led by Dr. Luc Mallet at the French Brain and Spinal Institute using funds granted by the FondaMental Foundation.